The present invention relates to a series of new derivatives of the compounds known as the "milbemycins", which derivatives are substituted at the 13-position. The invention also provides new methods and compositions using these compounds for agricultural and horticultural purposes, as well as processes for preparing them.
There are several classes of known compounds with a structure based on a 16-membered macrolide ring, which compounds are obtained by fermentation of various microorganisms or are obtained semi-synthetically by chemical derivatization of such natural fermentation products, and which exhibit acaricidal, insecticidal, anthelmintic and antiparasitic activities. The milbemycins and avermectins are examples of two such classes of known compounds, but various others also exist and are identified in the art by different names or code numbers. The names for these various macrolide compounds have generally been taken from the names or code numbers of the microorganisms which produce the naturally occurring members of each class, and these names have then been extended to cover the chemical derivatives of the same class, with the result that there has been no standardized systematic nomenclature for such compounds generally.
In order to avoid confusion, a standardized system of nomenclature will be used herein, which follows the normal rules for naming derivatives of organic compounds as recommended by the International Union of Pure and Applied Chemistry (IUPAC), Organic Chemistry Division, Commission on Nomenclature of Organic Chemistry, and which is based primarily on the hypothetical parent compound hereby defined as "milbemycin" and represented by the formula (A): ##STR2## wherein R.sup.a and R.sup.b both represent hydrogen atoms.
For the avoidance of doubt, formula (A) also shows the numbering of positions of the macrolide ring system applied to those positions most relevant to the compounds of the present invention and of the prior art.
The naturally produced milbemycins are a series of macrolide compounds known to have anthelmintic, acaricidal and insecticidal activities. Milbemycin D was disclosed in U.S. Pat. No. 4,346,171, where it was referred to as "Compound B-41D", and milbemycins A.sub.3 and A.sub.4 were disclosed in U.S. Pat. 3,950,360. These compounds may be represented by the above formula (A) in which R.sup.a at position 13 is a hydrogen atom and R.sup.b at position 25 is a methyl group, an ethyl group or an isopropyl group, these compounds being designated as milbemycin A.sub.3, milbemycin A.sub.4 and milbemycin D, respectively. The milbemycin analogs having a hydrogen atom at position 13 and substituted at position 25 with a sec-butyl or an isopropyl group, respectively, were disclosed in U.S. Pat. No. 4,173,571 as "13-deoxy-22,23-dihydroavermectin B.sub.1a aglycone" and "13-deoxy-22,23-dihydroavermectin B.sub.1 b aglycone"; and the corresponding 13-glycosylated compounds are known as "22,23-dihydro-avermectin B.sub.1a " and "22,23-dihydro-avermectin B.sub.1 b".
Subsequently, various derivatives of the original milbemycins and avermectins have been prepared and their activities investigated. For example, 5-esterified milbemycins have been disclosed in U.S. Pat. Nos. 4,199,569, 4,201,861, 4,206,205, 4,173,571, 4,171,314, 4,203,976, 4,289,760, 4,457,920, 4,579,864 and 4,547,491, in European Patent Publications 8184, 102,721, 115,930, 180,539 and 184,989 and in Japanese Patent Applications Kokai (i.e. as laid open to public inspection) 57-120589 and 59-16894.
13-Hydroxy-5-ketomilbemycin derivatives have been disclosed in U.S. Pat. No. 4,423,209. Milbemycin 5-oxime derivatives were disclosed in U.S. Pat. No. 4,547,520 and in European Patent Publication 203 832. Milbemycin 23-oxime derivatives were disclosed in European Patent Publication 259,779; and milbemycin derivatives having an oximino substituent at the 13-position were disclosed in European Patent Publications 165,029 and 341,972, and in PCT Publication WO 93/18041.
Several compounds in which the 13-hydroxy group has been esterified are disclosed in U.S. Pat. No. 4,959,386, which describes esters of various carboxylic acids. None of the carboxylic acid moieties at the 13-position of these prior art compounds have heterocyclyl substituents. 13-Acetoxymilbemycin derivatives, in which the acetoxy group can be substituted by various heterocyclylthio groups, are disclosed in European Patent Publication 549 273. European Patent Publication 246 739 discloses 13-alkanoic ester milbemycins which can be substituted at the .alpha.-position of the alkanoyl group by various moieties including arylmethyl, heterocyclylmethyl, phenoxy and heterocyclyloxy groups.
None of the carboxylic acid moieties at the 13-position in these prior art compounds have an alkoxyimino substituent, or have an aryl or heterocyclyl substituent having substituted-amino ring substituents.
A number of milbemycins having an ether group at the 13-position have been disclosed. Milbemycins having a phenylalkoxy group at the 13-position are disclosed in European Patent Publications 448 243, 444 964, 357 460 and 594 291.
13-Ether milbemycins in which the alkoxy group has an aryloxyimino or a heterocyclyloxyimino substituent have not been disclosed in the prior art.
The various classes of milbemycin-related macrolide compounds referred to above are all disclosed as having one or more types of activity as antibiotic, anthelmintic, ectoparasiticidal, acaricidal or other pesticidal agents. However, there is still a continuing need to provide such agents with improved activity against one or more classes of agricultural and horticulural pests.
It has now been discovered that the activity of such milbemycin-related derivatives can be improved by appropriately selecting the combination of substituents on the macrolide ring system, especially the substituents at position 13. In particular, it has now been found that the activity of the compounds can be improved upon by appropriate selection of certain highly specific ester and ether groups at the 13 position, as specified below. In general, the compounds of the present invention tend to have a better pesticidal activity than do the compounds of the prior art, and many of the compounds of the present invention have a very substantially better activity.